Mechanism of Hypopigmentary Diseases - We have recently reported the surprising finding that all 4 known major forms of oculocutaneous albinism (OCA) are in fact ER-processing/trafficking diseases stemming from the abortive processing and/or sorting of tyrosinase (the critical melanogenic enzyme). In OCA types 1-4, tyrosinases, either mutant (as in OCA1) or wild-type (as in OCA2, OCA3 and OCA4), are retained in the ER and prematurely degraded by proteasomes and/or are incorrectly sorted to melanosomes. This ER quality control system in melanocytes is exquisitely sensitive and detects even very minor perturbations in melanosomal proteins. These findings reveal why mutations in a number of pigment-related genes can have dramatic phenotypic effects on skin, hair and eye pigmentation, even in the presence of normal, catalytically functional tyrosinase. UV-Induced DNA Damage in Human Skin - we have completed the initial phase of a clinical study being performed in collaboration with the FDA to characterize the influence of skin pigment phenotype and phototype on UV-induced DNA damage. We have found that constitutive melanin in the skin does afford significant protection from UV damage, but not total protection, and even the darkest skin incurs some DNA damage. One surprising finding was that DNA damage is repaired more efficiently in darker skin, although whether this results from more efficient repair pathways or reflects the lower amounts of DNA damage that the system has to contend with, is not yet known. Another unexpected finding was that UV-induced apoptosis was significantly higher in dark skin than in light skin. Melanosomal Proteomics and Informatics - We have completed our project to characterize the proteome of melanosomes during their maturation. Determining the dynamics of proteins sorted to various stages of melanosomes has provided glimpses of the biogenic pathway of that organelle (which probably also occurs for other lysosome-related organelles, although not so easy to discern since they don't display obvious structural changes as do melanosomes). The intent of this project was to identify novel specific constituents of melanosomes that might serve as targets for malignant melanoma and/or identify other novel specific biomarkers of melanocytes. Regulation of Melanocyte Function - We have further clarified the role of how UV radiation and the MSH receptor (MC1R) regulate human pigmentation, how the expression and function of MC1R is regulated by its agonist (MSH) and its antagonist (ASP), and the signaling pathways involved in its regulation of melanocyte differentiation.